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(Cpmp) Note for Guidance on Repeated Dose Toxicity

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(Cpmp) Note for Guidance on Repeated Dose Toxicity The European Agency for the Evaluation of Medicinal Products Evaluation of Medicines for Human Use London, 27 July 2000 CPMP/SWP/1042/99 corr. COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP) NOTE FOR GUIDANCE ON REPEATED DOSE TOXICITY DISCUSSION IN THE SAFETY WORKING PARTY June 1998 – November 1999 TRANSMISSION TO THE CPMP December 1999 RELEASE FOR CONSULTATION December 1999 DEADLINE FOR COMMENTS March 2000 RE-DISCUSSION IN THE SAFETY WORKING PARTY June 2000 ADOPTION BY THE CPMP July 2000 DATE FOR COMING INTO OPERATION October 2000 This Note for guidance (3BS2a), first adopted in October 1983, has been revised to update the guidance on immunotoxicity provided in section 6. It has also been updated to refer to the Note for guidance on Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (ICH M3, CPMP/ICH/286/95) and other relevant ICH guidelines. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 20 E-mail: [email protected] http://www.emea.eu.int EMEA 2001 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged REPEATED DOSE TOXICITY 1. INTRODUCTION 1.1 Objectives The primary goal of repeated dose toxicity studies is to characterise the toxicological profile of the test compound following repeated administration. This includes identification of potential target organs of toxicity and exposure/response relationships and may include the potential reversibility of toxic effects. This information should be part of the safety assessment to support the conduct of human clinical trials and the approval of marketing authorisation. This note for guidance should be read together with the general requirements set out in Council Directive 75/318/EEC, as amended. This document should also be read in conjunction with other CPMP Notes for Guidance, especially, CPMP/ICH/300/95 Note for guidance on Duration of chronic toxicity testing in animals (Rodent and non-rodent toxicity testing), CPMP/ICH/384/95 Note for guidance on Toxicokinetics: A Guidance for assessing systemic exposure in toxicology studies, CPMP/ICH/286/95 Note for guidance on Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. 1.2 Scope This Note for guidance concerns the conduct of repeated dose toxicity studies of compounds intended for human use. For certain types of compounds, such as biotechnology derived compounds, vaccines and anticancer medicinal products, specific guidance is available (see CPMP/ICH/302/95 Note for guidance on Safety studies for biotechnological products, CPMP/SWP/465/95 Note for guidance on Pre-clinical pharmacological and toxicological testing of vaccines, CPMP/SWP/997/96 Note for guidance on the Pre-clinical evaluation of anticancer medicinal products). 2. GENERAL PRINCIPLES Repeated dose toxicity studies should be carried out in conformity with the provisions relating to good laboratory practice laid down by Council Directives 87/18/EEC and 88/320/EEC. The design of the study, including selection of test species, dose levels, route and frequency of administration, should be based on available pharmacodynamic, pharmacokinetic and toxicological information as well as the intended clinical use. The investigator should justify the selected study design. 3. GENERAL RECOMMENDATIONS ON SUBSTANCE QUALITY 3.1 Substance quality Each batch used in the repeated dose toxicity studies should be identified. The physico-chemical characteristics should be presented and certified for each batch and the stability of the material stated. Furthermore, the stability of the substance in the tested dose formulation should be known. The substance used in the repeated dose toxicity studies should present the same pattern of impurities as the product intended for marketing, when possible. Should the medicinal product intended for marketing have impurities significantly different from those in the test batches, either in terms of quality or quantity, these may need further qualification (see Notes for guidance on impurities: CPMP/ICH/142/95 Note for guidance on Impurities in new drug substances, CPMP/SWP/1042/99 corr. 1/9 EMEA 2001 CPMP/ICH/282/95 Note for guidance on Impurities in new drug products). 3.2 Excipients The toxicology and pharmacokinetics of an excipient used for the first time in the pharmaceutical field shall be investigated (cf Council Directive 75/318/EEC, as amended). In principle, the same pivotal studies as for a new active substance should be performed. In certain cases, studies with the active substance together with the excipient(s) used in the final product may be needed. 4. GENERAL RECOMMENDATIONS CONCERNING THE EXPERIMENTAL ANIMAL 4.1 Animal species Within the usual spectrum of laboratory animals used for toxicity testing, the species should be chosen based on their similarity to humans with regard to pharmacokinetic profile including biotransformation. Exposure to the main human metabolite(s) should be ensured. If this can not be achieved in toxicity studies with the parent compound, specific studies with the metabolite(s) should be considered. When the product administered is a pro-drug, its conversion to the active substance should be demonstrated in the species under study. Whenever possible, the selected species should be responsive to the primary pharmacodynamic effect of the substance. In certain cases e.g. when the pharmacodynamic effect by itself will cause toxicity, studies in disease models may be warranted. 4.2 Sexes Normally, equal numbers of male and female animals should be used. 4.3 Size of treatment groups The size of the treatment group should be sufficient to allow meaningful scientific interpretation of the data generated. However, ethical considerations as well as practical aspects are also of importance. The following should be considered: • Background knowledge concerning the ranges of variables to be studied in the species and strains used is also relevant to consideration of group size. • In case of interim sacrifice, the size of the treatment groups should be large enough to permit the sacrifice of animals at intervals before the end of the study without interfering with the final statistical analysis. • In case of a recovery period, the size of the treatment groups should be large enough to allow some animals to be retained at the completion of the period of dosing so that the reversibility of toxic changes at the end of the treatment may be evaluated 4.4 Number of species In general, repeated dose toxicity studies shall be carried out in two species of mammals, one of which must be a non-rodent (cf Council Directive 75/318/EEC, as amended). The use of one species is acceptable if it has been unequivocally demonstrated that other available species are irrelevant as models for human safety assessment. CPMP/SWP/1042/99 corr. 2/9 EMEA 2001 4.5 Animal husbandry A high standard of animal husbandry is required (cf The Council Directive on animal welfare 86/609/EEC and Council Decision on the European Convention on the protection of vertebrae animals, 1999/575/EC). The environmental conditions should be controlled. The diet and water should be of known quality and composition throughout the study period. These conditions should be recorded in the report. 5. GENERAL RECOMMENDATIONS CONCERNING DOSE AND ADMINISTRATION The dose regimen and route of administration should be chosen based on the intended clinical use with the aim to obtain sufficient exposure of the animals to the substance and its metabolites. In designing the study, all available information on pharmacodynamics, pharmacokinetics and toxicity of the medicinal product should be considered. When toxicity studies of three months duration or longer are necessary, it is recommended that a repeated dose toxicity study of two or four weeks duration is carried out in such a manner that it can serve as a dose-finding study for the longer term investigation. 5.1 Duration of administration The duration of repeated dose toxicity studies depends on the duration of the proposed therapeutic use in humans (see CPMP/ICH/286/95: Note for guidance on Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals and CPMP/ICH/300/95: Duration of chronic toxicity testing in animals (Rodent and non-rodent toxicity testing)). 5.2 Route of administration In general, the medicinal product should be administered by the same route as that intended for humans. Other routes of administration may be selected, if justified on the basis of pharmacological, pharmacokinetic/toxicokinetic and/or toxicological information. In addition to systemic toxicity, effects at the site of administration, and if different, the intended clinical site of administration should be evaluated (see Note for guidance on Non-clinical local tolerance testing of medicinal products Vol. III: Eudra/S/90/024). 5.3 Frequency of administration The frequency of administration should be determined on a case-by-case basis taking account of the intended clinical dosing regimen and the toxicological/pharmacokinetic/pharmacodynamic profile of the test compound. In some cases more frequent administration in animals than anticipated in clinical use may be appropriate. 5.4 Dose levels In general, the treatment should include • appropriate control group(s); in special cases a positive control group may be necessary • a low dose, sufficient to produce a pharmacodynamic effect or the desired therapeutic effect, or result in systemic exposure comparable with that expected at the intended clinical use • a high dose, selected to enable identification of target organ toxicity or other non-specific CPMP/SWP/1042/99 corr. 3/9 EMEA 2001 toxicity, or until limited by volume of dose • an intermediate dose, such as the geometric mean between the high and the low dose. Ideally, at the high dose level, the systemic exposure to the drug and/or principal metabolites should be a significant multiple of the anticipated clinical systemic exposure.
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